3,5-dimethylbenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】26775

【品名】3,5-dimethylbenzoic acid

【CA登记号】499-06-9

【分子式】C₉H₁₀O₂

【分子量】150.1772

【元素组成】C 71.98% H 6.71% O 21.31%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VIII)

4'-Methylacetophenone (I) was condensed with boiling dimethylformamide dimethylacetal, and the resulting enaminoketone (II) was cyclized to the isoxazole (III) with hydroxylamine O-sulfonic acid in MeOH. Benzylic bromination of (III) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromomethyl compound (IV). Subsequent alkylation of diphenylmethylene glycine ethyl ester (V) with (IV) under phase-transfer conditions, followed by acid deprotection furnished isoxazolylphenylalanine ethyl ester (VII). This compound was condensed with 3,5-dimethyl benzoic acid (VIII) using EDC and HOBt to give amide (IX). Further N-methylation of (IX) with MeI and NaH yielded (X), which was hydrolyzed with LiOH to the carboxylic acid (XI).

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241.
【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17145	1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone	122-00-9	C₉H₁₀O	详情	详情
(II)	26769	(E)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one		C₁₂H₁₅NO	详情	详情
(III)	26770	5-(4-methylphenyl)isoxazole		C₁₀H₉NO	详情	详情
(IV)	26771	5-[4-(bromomethyl)phenyl]isoxazole		C₁₀H₈BrNO	详情	详情
(V)	26772	ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate	69555-14-2	C₁₇H₁₇NO₂	详情	详情
(VI)	26773	ethyl 2-[(dibenzylene)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₇H₂₄N₂O₃	详情	详情
(VII)	26774	ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate		C₁₄H₁₆N₂O₃	详情	详情
(VIII)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(IX)	26776	ethyl 2-[(3,5-dimethylbenzoyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₃H₂₄N₂O₄	详情	详情
(X)	26777	ethyl 2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₄H₂₆N₂O₄	详情	详情
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247.
【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17145	1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone	122-00-9	C₉H₁₀O	详情	详情
(II)	26769	(E)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one		C₁₂H₁₅NO	详情	详情
(III)	26770	5-(4-methylphenyl)isoxazole		C₁₀H₉NO	详情	详情
(IV)	26771	5-[4-(bromomethyl)phenyl]isoxazole		C₁₀H₈BrNO	详情	详情
(V)	26772	ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate	69555-14-2	C₁₇H₁₇NO₂	详情	详情
(VI)	26773	ethyl 2-[(dibenzylene)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₇H₂₄N₂O₃	详情	详情
(VII)	26774	ethyl 2-amino-3-[4-(5-isoxazolyl)phenyl]propanoate		C₁₄H₁₆N₂O₃	详情	详情
(VIII)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(IX)	26776	ethyl 2-[(3,5-dimethylbenzoyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₃H₂₄N₂O₄	详情	详情
(X)	26777	ethyl 2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(5-isoxazolyl)phenyl]propanoate		C₂₄H₂₆N₂O₄	详情	详情
(XI)	26778	N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine		C₂₂H₂₂N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X). This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII). Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.

参考文献中间体

合成目标

【1】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 .
【2】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	47946	2-(3,4-dichlorophenyl)piperazine		C₁₀H₁₂Cl₂N₂	详情	详情
(IX)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(X)	47950	[3-(3,4-dichlorophenyl)-1-piperazinyl](3,5-dimethylphenyl)methanone		C₁₉H₂₀Cl₂N₂O	详情	详情
(XI)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(XIII)	34808	1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine	50541-93-0	C₁₂H₁₈N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

In a related method, the 2-arylpiperazine (IV) was first protected as the 4-tert-butyl carbamate (XIV) upon treatment with di-tert-butyl dicarbonate in MeOH at -78 C. Subsequent acylation of (XIV) with bromoacetyl bromide (XI) produced the bromo amide (XV), which was then condensed with the aminopiperidine (XIII), yielding the glycinamide derivative (XVI). Acidic cleavage of the Boc group of (XVI) afforded the 1-acyl piperazine (XVII). This was finally coupled with 3,5-dimethylbenzoic acid using EDC and HOBt.

参考文献中间体

合成目标

【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	47946	2-(3,4-dichlorophenyl)piperazine		C₁₀H₁₂Cl₂N₂	详情	详情
(IX)	26775	3,5-dimethylbenzoic acid	499-06-9	C₉H₁₀O₂	详情	详情
(XI)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(XIII)	34808	1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine	50541-93-0	C₁₂H₁₈N₂	详情	详情
(XIV)	47952	tert-butyl 3-(3,4-dichlorophenyl)-1-piperazinecarboxylate		C₁₅H₂₀Cl₂N₂O₂	详情	详情
(XV)	47953	tert-butyl 4-(2-bromoacetyl)-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate		C₁₇H₂₁BrCl₂N₂O₃	详情	详情
(XVI)	47954	tert-butyl 4-[2-[(1-benzyl-4-piperidinyl)amino]acetyl]-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate		C₂₉H₃₈Cl₂N₄O₃	详情	详情
(XVII)	47955	2-[(1-benzyl-4-piperidinyl)amino]-1-[2-(3,4-dichlorophenyl)-1-piperazinyl]-1-ethanone		C₂₄H₃₀Cl₂N₄O	详情	详情

Extended Information